BACKGROUND: Holoprosencephaly (HPE) is the most common forebrain defect in humans. It results from incomplete midline cleavage of the prosencephalon. METHODS: A large European series of 645 HPE probands (and 699 relatives), consisting of 51% fetuses and 49% liveborn children, is reported. RESULTS: Mutations in the four main genes involved in HPE (SHH, ZIC2, SIX3, TGIF) were identified in 25% of cases. The SHH, SIX3, and TGIF mutations were inherited in more than 70% of these cases, whereas 70% of the mutations in ZIC2 occurred de novo. Moreover, rearrangements were detected in 22% of the 260 patients screened by array comparative genomic hybridisation. 15 probands had two mutations providing additional support for the 'multiple-hit process' in HPE. There was a positive correlation between the severity of the brain malformation and facial features for SHH, SIX3, and TGIF, but no such correlation was found for ZIC2 mutations. The most severe HPE types were associated with SIX3 and ZIC2 mutations, whereas microforms were associated with SHH mutations. The study focused on the associated brain malformations, including neuronal migration defects, which predominated in individuals with ZIC2 mutations, and neural tube defects, which were frequently associated with ZIC2 (rachischisis) and TGIF mutations. Extracraniofacial features were observed in 27% of the individuals in this series (up to 40% of those with ZIC2 mutations) and a significant correlation was found between renal/urinary defects and mutations of SHH and ZIC2. CONCLUSIONS: An algorithm is proposed based on these new phenotype-genotype correlations, to facilitate molecular analysis and genetic counselling for HPE.
BACKGROUND:Holoprosencephaly (HPE) is the most common forebrain defect in humans. It results from incomplete midline cleavage of the prosencephalon. METHODS: A large European series of 645 HPE probands (and 699 relatives), consisting of 51% fetuses and 49% liveborn children, is reported. RESULTS: Mutations in the four main genes involved in HPE (SHH, ZIC2, SIX3, TGIF) were identified in 25% of cases. The SHH, SIX3, and TGIF mutations were inherited in more than 70% of these cases, whereas 70% of the mutations in ZIC2 occurred de novo. Moreover, rearrangements were detected in 22% of the 260 patients screened by array comparative genomic hybridisation. 15 probands had two mutations providing additional support for the 'multiple-hit process' in HPE. There was a positive correlation between the severity of the brain malformation and facial features for SHH, SIX3, and TGIF, but no such correlation was found for ZIC2 mutations. The most severe HPE types were associated with SIX3 and ZIC2 mutations, whereas microforms were associated with SHH mutations. The study focused on the associated brain malformations, including neuronal migration defects, which predominated in individuals with ZIC2 mutations, and neural tube defects, which were frequently associated with ZIC2 (rachischisis) and TGIF mutations. Extracraniofacial features were observed in 27% of the individuals in this series (up to 40% of those with ZIC2 mutations) and a significant correlation was found between renal/urinary defects and mutations of SHH and ZIC2. CONCLUSIONS: An algorithm is proposed based on these new phenotype-genotype correlations, to facilitate molecular analysis and genetic counselling for HPE.
Authors: Sophia M Bous; Benjamin D Solomon; Luitgard Graul-Neumann; Heidemarie Neitzel; Emily E Hardisty; Maximilian Muenke Journal: Clin Dysmorphol Date: 2012-10 Impact factor: 0.816
Authors: F Démurger; L Pasquier; C Dubourg; V Dupé; I Gicquel; C Evain; L Ratié; S Jaillard; M Beri; B Leheup; J Lespinasse; D Martin-Coignard; S Mercier; C Quelin; P Loget; P Marcorelles; A Laquerrière; C Bendavid; S Odent; V David Journal: Mol Syndromol Date: 2013-08-01
Authors: C Coutton; B Poreau; F Devillard; C Durand; S Odent; C Rozel; G Vieville; F Amblard; P-S Jouk; V Satre Journal: Mol Syndromol Date: 2013-10-02
Authors: Azeez Butali; Peter A Mossey; Wasiu L Adeyemo; Mekonen A Eshete; Lord J J Gowans; Tamara D Busch; Deepti Jain; Wenjie Yu; Liu Huan; Cecelia A Laurie; Cathy C Laurie; Sarah Nelson; Mary Li; Pedro A Sanchez-Lara; William P Magee; Kathleen S Magee; Allyn Auslander; Frederick Brindopke; Denise M Kay; Michele Caggana; Paul A Romitti; James L Mills; Rosemary Audu; Chika Onwuamah; Ganiyu O Oseni; Arwa Owais; Olutayo James; Peter B Olaitan; Babatunde S Aregbesola; Ramat O Braimah; Fadekemi O Oginni; Ayodeji O Oladele; Saidu A Bello; Jennifer Rhodes; Rita Shiang; Peter Donkor; Solomon Obiri-Yeboah; Fareed Kow Nanse Arthur; Peter Twumasi; Pius Agbenorku; Gyikua Plange-Rhule; Alexander Acheampong Oti; Olugbenga M Ogunlewe; Afisu A Oladega; Adegbayi A Adekunle; Akinwunmi O Erinoso; Olatunbosun O Adamson; Abosede A Elufowoju; Oluwanifemi I Ayelomi; Taiye Hailu; Abiye Hailu; Yohannes Demissie; Miliard Derebew; Steve Eliason; Miguel Romero-Bustillous; Cynthia Lo; James Park; Shaan Desai; Muiawa Mohammed; Firke Abate; Lukman O Abdur-Rahman; Deepti Anand; Irfaan Saadi; Abimibola V Oladugba; Salil A Lachke; Brad A Amendt; Charles N Rotimi; Mary L Marazita; Robert A Cornell; Jeffrey C Murray; Adebowale A Adeyemo Journal: Hum Mol Genet Date: 2019-03-15 Impact factor: 6.150
Authors: Lucilene A Ribeiro; Erich Roessler; Ping Hu; Daniel E Pineda-Alvarez; Nan Zhou; Marypat Jones; Settara Chandrasekharappa; Antonio Richieri-Costa; Maximilian Muenke Journal: Birth Defects Res A Clin Mol Teratol Date: 2012-07-27